CN109010249A - Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application - Google Patents
Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application Download PDFInfo
- Publication number
- CN109010249A CN109010249A CN201710425912.7A CN201710425912A CN109010249A CN 109010249 A CN109010249 A CN 109010249A CN 201710425912 A CN201710425912 A CN 201710425912A CN 109010249 A CN109010249 A CN 109010249A
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- CN
- China
- Prior art keywords
- pharmaceutical composition
- injection
- dabigatran etcxilate
- pharmaceutically acceptable
- dabigatran
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002347 injection Methods 0.000 title claims abstract description 64
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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Abstract
The present invention relates to a kind of injection dabigatran etcxilate pharmaceutical compositions and its preparation method and application.The dabigatran etcxilate pharmaceutical composition includes: (1) active material dabigatran etcxilate as shown in Formulas I -2；(2) pharmaceutically acceptable solvent；And (3) other pharmaceutically acceptable auxiliary materials being optionally present.Experiments have shown that injection dabigatran etcxilate pharmaceutical composition indices of the invention meet related drug regulation, safety, solubility and long-time stability are all showed well.Medicine generation test display, injection dabigatran etcxilate pharmaceutical composition of the invention can keep internal suitable blood concentration and duration for the treatment of after administration, and pH value is shown as neutral, greatly reduces the stimulation to gastrointestinal tract.Preparation process of the present invention is simple, facilitates feasible, reproducible, lower production costs, it is easy to realize industrialization large-scale production.
Description
Technical field
The present invention relates to the sustained release preparations of marketed drug, and in particular to a kind of injection dabigatran etcxilate pharmaceutical composition
And its preparation method and application.
Background technique
Currently, cardiovascular disease is one of the main reason for leading to human death, its main aspect is thrombus shape
At being to be caused blood coagulation by a series of complex reaction and caused.Blood clotting is a kind of protection mechanism of organism, whereby can be quickly
And the defect of vascular wall reliably " is sealed ", therefore to avoid blood loss or limit can be preferably minimized, maintains normal haemostasis
Effect, i.e. bleeding and coagulation homeostasis, the regulation by a complex mechanism.Not modulated coagulation system activation lacks activation
The inhibiting effect of process all may cause a variety of diseases and complication, such as phlebothrombosis, deep vein thrombosis, pulmonary embolism, artery
Atherosis, acute coronary syndrome, cranial vascular disease etc..
The oral anticoagulant object listed mainly has direct thrombin inhibitor, Xa factor inhibitor, the suppression of the IX factor
Preparation, tissue factor inhibitor and novel vitamin K antagon etc..Wherein dabigatran etcxilate is a kind of oral, selectivity height
Thrombin inhibitor is imitated, clinic, which is proved it, can substitute warfarin as in the non-valvular atrial fibrillation patient of prevention
Wind and systemic embolism simultaneously substitute Enoxaparin Sodium as the preferred use for preventing main shaping postoperative patient venous thromboembolic event
Medicine.
Dabigatran (Dabigatran, structure is as shown in following formula I -1) is a kind of selective high performance thrombin inhibitor
Object, but due to the presence of strong basicity amidino groups in its molecule, it is oral to absorb.To improve its bioavilability, need to distinguish
Free carboxy in dabigatran molecule is transformed into ethyl ester, amidino groups is transformed into the own ester of carbamic acid, obtain its bi precursor medicine
Object -- dabigatran etcxilate (Dabigatran Etexilate, structure is as shown in following formula I -2).After dabigatran etcxilate is oral, through stomach
Then intestinal absorption is converted into active material dabigatran in vivo, in conjunction with the fibrin specific site of fibrin ferment, prevent
Fibrinogen is cracked into fibrin, to block the final step and thrombosis of blood coagulation waterfall network, plays anticoagulation
Effect.
Based on the studies above, German Boehringer Ingelheim company further develops dabigatran etcxilate mesylate (knot
Structure is as shown in formula I above -3), it takes the lead in listing in Germany and Britain in April, 2008, is the head listed over 50 years after warfarin
A new category oral anticoagulant object, it is a kind of direct thrombin inhibitor, have it is orally available, potent, without special detection,
The advantages that drug interaction is few.FDA on October 19 announces the official approval drug list marketing, trade name within 2010
Pradaxa, Chinese name Thailand Bi Quan, indication are the stroke prevention that auricular fibrillation causes.Hereafter, auricular fibrillation indication obtains successively
Obtain the approval of the countries and regions such as Canadian, Japanese, European Union.The dabigatran ester formulation listed at present is to contain the dabigatran
The pellt capsule of ester mesylate.
Patent ZL 03805473.6 discloses a kind of dabigatran etcxilate combination of oral medication, is hard capsules dosage form,
Inside is the core material being made of tartaric acid, successively wraps up separation layer and active material layer outside the core material.The hard rubber wafer
It is not only difficult in technique, and bioavilability is very low (3~7%) in human body.Compared with reference capsule, going
Oral administration biaavailability when directly taking particle therein except hydroxypropyl methyl cellulose (HPMC) capsule shell may go out
It is now up to 75% increase, leads to bleeding or even life danger.Therefore, it needs to give much attention to protect during clinical use
The integrality of HPMC capsule is held to avoid being not intended to lead to increasing for dabigatran etcxilate bioavilability.So should inform that patient can not
It opens capsule and individually takes particle therein (such as be dispersed in food or be placed in beverage and take), to avoid bleeding risk；
Since the effective concentration of its safety, half-life period are shorter (excretion is quickly), patient need to take being somebody's turn to do for 110mg or 150mg twice daily
Capsule medicament；And the prescription medicine acidity is stronger, is easy stimulating gastrointestinal road, eats particularly with some with digestive tract ulcer, stomach
The patient of the diseases such as road reflux, a large amount of unabsorbed dabigatran easily cause patient's gastrointestinal tract uncomfortable, increase side effect (tool
Body is referring to the FDA declaration material of dabigatran etcxilate and the drug operation instructions of FDA).
Summary of the invention
For the above reason, on the one hand, the present invention designs a kind of injection delivery systems of slow release dabigatran etcxilate, tool
Body is to provide a kind of injection dabigatran etcxilate pharmaceutical composition, thus suitable blood concentration and treatment in vivo after keeping administration
Duration, this is to improve dabigatran prevention of deep vein thrombosis and pulmonary embolism (in progress hip joint or replacement knee in arthroplasty
Later), the effective way for the thrombophlebitis (deep vein thrombosis) that treatment has been formed；Very big possible reduction stomach and intestine simultaneously
The side effect in road.
The present invention is found surprisingly that, injection delivery systems of the invention, i.e., the described injection dabigatran etcxilate pharmaceutical composition
The pharmacokinetics in rats curve of object is substantially better than oral administration (dabigatran etcxilate), after oral administration 8 hours, in vivo just
It can't detect dabigatran blood concentration completely, and still in vivo can after using of the invention injection delivery systems 24 hours
Detect the blood concentration of dabigatran；Not only exposed amount increases substantially, while Drug-time curve is also more gentle.
Specifically, injection dabigatran etcxilate pharmaceutical composition of the present invention includes the active matter as shown in Formulas I -2
Matter dabigatran etcxilate and pharmaceutically acceptable solvent, for example including but be not limited to, water for injection, physiological saline, PBS are slow
Fliud flushing or pharmaceutically acceptable oil phase solvent and their mixture.
The pharmaceutically acceptable oil phase solvent is selected from: olive oil, sesame oil, Emulsifier EL-60, peanut oil, poly- second
Glycol (PEG-400), Solutol HS15 (solutol), ethyl oleate and their mixture.
In addition, in order to better pharmacy characteristic, injection dabigatran etcxilate pharmaceutical composition of the invention may be used also
It is optionally present other at least one pharmaceutically acceptable auxiliary materials.Other described auxiliary materials be selected from small molecule or high-molecular compound with
And their mixture, for example including but be not limited to, sodium chloride, glucose, glycerol, mannitol, lactose, trehalose, carboxymethyl
Sodium cellulosate, hypromellose, hydroxypropyl-cyclodextrin, Tween 80, poloxamer, Tai Luoshamu, polyethylene glycol, poly- second
Glycol stearate 15, PEG- cholesterol, PEG- cholesterol derivative, PEG- vitamin A, PEG- vitamin E, vinyl acetate
Ester, pyrrolidones, gelatin, casein, Dextran 40, cholesterol, glycerine, colloidal silicon dioxide, gum arabic, Radix Astragali
Glue, peach gum, carbomer, stearic acid, calcium stearate, hexadecanol-octadecyl alcolol mixture, cetomacrogol emulsifying wax, Sorbitan
Alcohol, polyoxyethylene alkyl ether, castor oil derivatives (cremophore EL), polyoxyethylene sorbitan rouge
Fat acid esters, Myrj 45, phosphate, dodecyl sodium sulfate, calcium carboxymethylcellulose, carboxy-propyl cellulose, first
Base cellulose, hydroxyethyl cellulose, noncrystalline cellulose, hard acid magnalium, polyvinyl alcohol, dioctyl sulfosuccinate, sodium sulfo group
Dialkyl succinate, lauryl sodium sulfate, alkyl aryl polyether sulphonic acid ester, sucrose stearate and sucrose distearate
Mixture, vinylpyrrolidone-methacrylic acid -2- dimethylaminoethyl dimethyl suflfate, amine, amine oxide, amine salt, three second
Hydramine, benzalkonium chloride, polymethyl methacrylate bromination trimethylammonium, dodecyltrimethylammonium bromide, cetyltrimethylammonium
Ammonium, chlorination three (cetyl) methyl ammonium, alkyl-front three ammonium salt, dialkyl group-diformazan ammonium salt, dodecyltrimethyl,
Alkyl dimethyl ammonium halide, bromination decyl trimethyl ammonium, bromination dodecyltriethyl ammonium, Tetrabutylammonium bromide, cylite
Base trimethyl ammonium, quaternized polyoxyethanyl alkylamine, methylation quaternary ammonium polymer, protonation quaternary ammonium acrylamide, bromination 16
Alkyl pyridine, cetyl pyridinium, acid imide pyrroles salt, sulphur compound, cation guar gum and theirs is mixed
Close object.
In injection dabigatran etcxilate pharmaceutical composition of the invention, by weight percentage, active material Da Bijia
The content of group ester I-2 is the 0.001%~85% of injection dabigatran etcxilate pharmaceutical composition total weight, preferably 0.1%~
80%, more preferable 1%~50%；Remaining for pharmaceutically acceptable solvent and be optionally present pharmaceutically acceptable other are auxiliary
Material.
The active material dabigatran etcxilate of the present invention as shown in Formulas I -2, while further including its pharmaceutically acceptable salt.
The pharmaceutically acceptable salt refers to that the compound can form officinal salt with inorganic acid or organic acid, and wherein inorganic acid is such as
Hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid；The organic acid such as methanesulfonic acid, three are the richest in sulfonic acid, second
Sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, oxalic acid, maleic acid, citric acid, tartaric acid, lactic acid, succinic acid, malic acid.
On the other hand, the present invention also provides a kind of preparation methods of injection dabigatran etcxilate pharmaceutical composition, including with
Lower step:
It weighs the active material dabigatran etcxilate as shown in Formulas I -2 of recipe quantity and/or pharmaceutically acceptable other is auxiliary
Material, is added suitable pharmaceutically acceptable solvent, stirring and dissolving continues to be added to recipe quantity, after mixing evenly, add thereto
Enter appropriate medicinal carbon to be adsorbed, then use filtering with microporous membrane decarburization, then through filtering with microporous membrane degerming to get.
The additive amount of the medicinal carbon is the 0.01%~0.5%, preferably 0.01%~0.5% of overall solution volume,
More preferable 0.1%~0.3%, most preferably 0.1%~0.2%, w/v.
It is preferred that the filtering with microporous membrane with 0.45 μm of Φ takes off charcoal, 0.22 μm of Φ of filtering with microporous membrane degerming is used again later.
Optional, after filtration sterilization, carry out frozen dried.The frozen dried is well known to those skilled in the art pharmacy
Technique, wherein pre-freezing temperature is -20 DEG C~-60 DEG C, and the pre-freeze time is 2h~10h；Lyophilization temperature is -40 DEG C~0 DEG C, is risen
Magnificent drying time is 10h~40h；Parsing-desiccation temperature is 0 DEG C~30 DEG C, and the parsing-desiccation time is 3h~40h.
Injection dabigatran etcxilate pharmaceutical composition obtained according to the method for the present invention, can be oily liquids, can also be with
It is solid powder such as particulate matter or freeze-dried powder form, it when in use only need to be by itself and solvent for injection such as water for injection, life
Salt water, PBS buffer solution or pharmaceutically acceptable oil phase solvent and their mixture etc. is managed to redissolve.
The third aspect, the present invention also provides the injection dabigatran etcxilate pharmaceutical compositions to treat or prevent such as in preparation
Purposes in the medicament of lower illness, the illness include but is not limited to, such as:
(a) deep vein thrombosis and pulmonary embolism；And/or
(b) venous thromboembolism that has been formed, acute coronary syndrome, acute deep venous thrombosis, pulmonary embolism and
Recur deep vein thrombosis.
" injection " of the present invention, which refers to, is different from oral administration, but passes through the administration route of injection system, institute
Stating injection system may include but be not limited to, such as intravenous injection, subcutaneous injection, intracutaneous injection, intramuscular injection, the injection of vertebra chamber
Deng.Those skilled in the art can suitably select different drug administration by injection approach as the case may be, by dabigatran of the invention
Ester pharmaceutical composition carries out drug administration by injection.
Unless otherwise specified, pharmaceutically acceptable solvent of the present invention, and what is be optionally present can pharmaceutically connect
Other auxiliary materials received are " injection " medical/medicinal specification, such as water for injection, injection physiological saline, injection PBS delay
Liquid storage, oil for injection (such as injection olive oil, injection castor oil) etc., they are this field routine articles, the city Jun Ke
Sell acquisition.
Experiments have shown that injection dabigatran etcxilate pharmaceutical composition indices of the invention meet related drug rule
Fixed, safety, solubility and long-time stability all show well.Medicine generation test display, injection dabigatran etcxilate of the invention
Pharmaceutical composition can keep internal suitable blood concentration and duration for the treatment of after administration.And injection of the invention reach than
Add group ester pharmaceutical composition pH value for neutrality, relative to the commercial product Pradaxa capsule for showing as strong acidity, drops significantly
The low stimulation to gastrointestinal tract, has broad application prospects.And product of the present invention preparation process is simple, conveniently may be used
Row, reproducible, lower production costs, it is easy to realize industrialization large-scale production.
Detailed description of the invention
Attached drawing described herein is only used to provide further understanding of the present invention, and is constituted part of this application, and
It does not constitute an undue limitation on the present invention, in which:
Fig. 1 is that the change of pharmacokinetics of each drug under different way of administration (rat oral gavage or subcutaneous injection) is bent
Line.
Specific embodiment
Below with reference to appended the drawings and specific embodiments, the present invention will be described in detail, it should be appreciated that exemplary embodiment is only used
Explain the present invention, but not as a limitation of the invention.It should also be appreciated by one skilled in the art that the present invention is not by following
The limitation of embodiment, basic principles and main features and advantage only of the invention described in following embodiments and specification,
Without departing from the spirit and scope, various changes and improvements may be made to the invention, these changes and improvements are all fallen
Enter in the scope of the present invention.The scope of protection of present invention is defined by the appended claims and its equivalent.
Unless otherwise indicated, technical term used herein and scientific words are this field routine term.In addition, appointing
What method similar to or equal to what is recorded and material all can be applied in the present invention.The percentage is usually attached most importance to
% is measured, unless expressly stated otherwise,.
Compound I-1, I-2, I-3, I-4, I-5 can be synthesized according to existing known references, other experiment reagents, such as without spy
Different explanation, is commercial product.
Embodiment 1 prepares injection dabigatran etcxilate pharmaceutical composition 1
1) prescription: based on 1000 bottles (specification: 40mg/ bottles)
Active material dabigatran etcxilate I-2 40g
Solutol HS15 150mL
PBS buffer solution 850mL
2) preparation method:
The active material dabigatran etcxilate I-2 and Solutol HS15 of recipe quantity are weighed, it is suitable that PBS buffer solution is added
It measures, after stirring and dissolving, continues to be added to recipe quantity, after mixing evenly, add the medicinal carbon of amount of solution 0.1% (w/v), stir
After mixing absorption 30 minutes, charcoal is taken off with 0.45 μm of Φ of filtering with microporous membrane, is removed again with 0.22 μm of Φ of filtering with microporous membrane later
Bacterium.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get injection dabigatran etcxilate pharmaceutical composition 1 of the invention.
Embodiment 2 prepares injection dabigatran etcxilate pharmaceutical composition 2
1) prescription: based on 1000 bottles (specification: 40mg/ bottles)
Active material dabigatran etcxilate I-2 40g
Olive oil 1000mL
2) it prepares:
The active material dabigatran etcxilate I-2 of recipe quantity is weighed, addition olive oil is appropriate, after stirring and dissolving, continues to add
To recipe quantity, after mixing evenly, the medicinal carbon of addition amount of solution 0.1% (w/v) uses Φ after stirring and adsorbing 30 minutes
0.45 μm of filtering with microporous membrane takes off charcoal, then uses 0.22 μm of Φ of miillpore filter filtration sterilization again.Most afterwards through packing, tamponade,
Packaging is after rolling lid, full inspection qualification to get injection dabigatran etcxilate pharmaceutical composition 2 of the invention.
Embodiment 3 prepares injection dabigatran etcxilate pharmaceutical composition 3
1) prescription: based on 1000 bottles (specification: 40mg/ bottles)
Active material dabigatran etcxilate I-2 40g
Polyethylene glycol PEG-400 1000mL
2) it prepares:
The active material dabigatran etcxilate I-2 of recipe quantity is weighed, addition polyethylene glycol PEG-400 is appropriate, after stirring and dissolving,
Continue to be added to recipe quantity, after mixing evenly, the medicinal carbon of addition amount of solution 0.1% (w/v), stirring and adsorbing 30 minutes
Afterwards, charcoal is taken off with 0.45 μm of Φ of filtering with microporous membrane, uses 0.22 μm of Φ of miillpore filter filtration sterilization again later.Most afterwards through dividing
Dress, tamponade are packed after rolling lid, full inspection qualification to get injection dabigatran etcxilate pharmaceutical composition 3 of the invention.
Embodiment 4 prepares injection dabigatran etcxilate pharmaceutical composition 4
1) prescription: based on 1000 bottles (specification: 40mg/ bottles)
Active material dabigatran etcxilate I-2 40g
Emulsifier EL-60 150mL
PBS buffer solution 850mL
2) it prepares:
The active material dabigatran etcxilate I-2 and Emulsifier EL-60 of recipe quantity are weighed, addition PBS buffer solution is appropriate,
After stirring and dissolving, continue to be added to recipe quantity, after mixing evenly, adds the medicinal carbon of amount of solution 0.1% (w/v), stirring
After absorption 30 minutes, charcoal is taken off with 0.45 μm of Φ of filtering with microporous membrane, uses 0.22 μm of Φ of filtering with microporous membrane degerming again later.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get injection dabigatran etcxilate pharmaceutical composition 4 of the invention.
Embodiment 5 prepares injection dabigatran etcxilate pharmaceutical composition 5
1) prescription: based on 1000 bottles (specification: 40mg/ bottles)
Active material dabigatran etcxilate I-2 40g
Dextran 40 100mL
Physiological saline 900mL
2) it prepares:
The active material dabigatran etcxilate I-2 and Dextran 40 of recipe quantity are weighed, addition physiological saline is appropriate, stirs molten
Xie Hou continues to add to recipe quantity, after mixing evenly, then adds the medicinal carbon of amount of solution 0.1% (w/v), stirring and adsorbing
After 30 minutes, charcoal is taken off with 0.45 μm of Φ of filtering with microporous membrane, uses 0.22 μm of Φ of filtering with microporous membrane degerming again later.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get injection dabigatran etcxilate pharmaceutical composition 5 of the invention.
Embodiment 6 prepares injection dabigatran etcxilate pharmaceutical composition 6
1) prescription: based on 1000 bottles (specification: 133mg/ bottles)
Active material dabigatran etcxilate I-2 133.3g
Solutol HS15 150mL
PBS buffer solution 850mL
2) it prepares:
The active material dabigatran etcxilate I-2 and Solutol HS15 of recipe quantity are weighed, it is water-soluble that PBS buffering is added
Appropriate liquid after stirring and dissolving, continues to be added to recipe quantity, stir evenly, and the medicinal work of amount of solution 0.1% (w/v) is then added
Property charcoal, after stirring and adsorbing 30 minutes, take off charcoal with 0.45 μm of Φ of filtering with microporous membrane, use 0.22 μm of Φ of miillpore filter again later
Filtration sterilization.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get injection dabigatran etcxilate pharmaceutical composition 6 of the invention.
Embodiment 7 prepares injection dabigatran etcxilate pharmaceutical composition 7
1) prescription: based on 1000 bottles (specification: 267mg/ bottles)
Active material dabigatran etcxilate I-2 266.7g
Solutol HS15 150mL
PBS buffered aqueous solution 850mL
2) it prepares:
The active material dabigatran etcxilate I-2 and Solutol HS15 of recipe quantity are weighed, it is water-soluble that PBS buffering is added
Appropriate liquid after stirring and dissolving, continues to be added to recipe quantity, stir evenly, and the medicinal work of amount of solution 0.1% (w/v) is then added
Property charcoal, after stirring and adsorbing 30 minutes, with 0.45 μm of filtering with microporous membrane of Φ take off charcoal, later again use 0.22 μm of filtering with microporous membrane of Φ
Degerming.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get injection dabigatran etcxilate pharmaceutical composition 7 of the invention.
Comparative example 1 prepares dabigatran etcxilate mesylate injection
1) prescription: based on 1000 bottles (specification: 40mg/ bottles, in terms of dabigatran)
Active material dabigatran etcxilate mesylate I-3 46g
Water for injection 1000mL
2) it prepares:
The active material dabigatran etcxilate mesylate I-3 of recipe quantity is weighed, addition water for injection is appropriate, stirring and dissolving
Afterwards, continue to be added to recipe quantity, stir evenly, then add the medicinal carbon of amount of solution 0.1% (w/v), stirring and adsorbing 30
After minute, charcoal is taken off with 0.45 μm of Φ of filtering with microporous membrane, uses 0.22 μm of Φ of filtering with microporous membrane degerming again later.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get dabigatran etcxilate mesylate injection.
Comparative example 2 prepares dabigatran injection
1) prescription: based on 1000 bottles (specification: 40mg/ bottles, in terms of dabigatran)
Active material dabigatran I-1 30g
Solutol HS15 150mL
PBS buffer solution 850mL
2) it prepares:
The active material dabigatran I-1 and Solutol HS15 of recipe quantity are weighed, it is suitable that PBS buffer solution is added
It measures, after stirring and dissolving, continues to be added to recipe quantity, stir evenly, the medicinal carbon of amount of solution 0.1% (w/v) is then added,
After stirring and adsorbing 30 minutes, charcoal is taken off with 0.45 μm of Φ of filtering with microporous membrane, uses 0.22 μm of Φ of filtering with microporous membrane again later
Degerming.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get dabigatran injection.
Comparative example 3 prepares dabigatran etexilate intermediate injection 1
1) prescription: based on 1000 bottles (specification: 40mg/ bottles, in terms of dabigatran)
Active material dabigatran etexilate intermediate I-4 38.2g
Solutol HS15 150mL
PBS buffer solution 850mL
2) it prepares:
The active material dabigatran etexilate intermediate I-4 and Solutol HS15 of recipe quantity are weighed, it is slow that PBS is added
Solution of washing by water is appropriate, after stirring and dissolving, continues to be added to recipe quantity, stir evenly, and is then added amount of solution 0.1% (w/v)
Medicinal carbon after stirring and adsorbing 30 minutes, takes off charcoal with 0.45 μm of filtering with microporous membrane of Φ, later again with 0.22 μm of micropore filter of Φ
Film filtration sterilization.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get dabigatran etexilate intermediate injection 1.
Comparative example 4 prepares dabigatran etexilate intermediate injection 2
1) prescription: based on 1000 bottles (specification: 40mg/ bottles, in terms of dabigatran)
Active material dabigatran etexilate intermediate I-5 31.8g
Solutol HS15 150mL
PBS buffer solution 850mL
2) it prepares:
The active material dabigatran etexilate intermediate I-5 and Solutol HS15 of recipe quantity are weighed, it is slow that PBS is added
Solution of washing by water is appropriate, after stirring and dissolving, continues to be added to recipe quantity, stir evenly, and is then added amount of solution 0.1% (w/v)
Medicinal carbon after stirring and adsorbing 30 minutes, takes off charcoal with 0.45 μm of Φ of filtering with microporous membrane, micro- with 0.22 μm of Φ again later
Hole filter membrane filtration sterilization.
Then product after above-mentioned filtration sterilization is put into labconco FreeZone freeze dryer and carries out frozen dried.Most
By packing, tamponade, roll lid, full inspection it is qualified after packaging to get dabigatran etexilate intermediate injection 2.
Pharmacokinetic Evaluation
To sample made from above-described embodiment 1~7 and comparative example 1~4 carry out pharmacokinetic trial, the method for use and
Instrument is as follows:
(male, 6-8 week old are purchased from the western Poole-Bi Kai laboratory animal in Shanghai Co., Ltd to healthy adult SD rat, move
Object production licence number SCXK (Shanghai) 2013-0016), administration fasted for one day prior can't help water.3 subcutaneous rat (or stomach-filling) administrations
3mg/kg (in terms of dabigatran) is configured to 0.6mg/mL (0.3mg/mL) (with dabigatran with corresponding solvent (or formula)
Meter) solution (or suspension), before administration (0h) and be administered after 5min, 15min, 30min, 1.0,2.0,4.0,8.0,
24.0h is taken a blood sample 200uL by eye socket, anticoagulant heparin, and 8000rpm is centrifuged 6min at 4 DEG C, and blood plasma is then transferred to another sample
Guan Zhong is stored at -20 DEG C.
HPLC: ultra performance liquid chromatography system (Waters company, ACQUITY UPLC), including binary solvent manager
(ACQUITY UPLC Binary Solvent Manager), sample manager (ACQUITY UPLC Autosampler
Mod.), high-throughput sample tissue manager (ACQUTIY UPLC Sample Organizer), high temperature column oven (ACQUITY
UPLC Column Heater HT)。
MS:(API 4000, Applied biosystems), electric spray ion source (ESI), series connection quadrupole rod quality point
Parser.Data processing system is Analyst software (Applied biosystems, software version number 1.5.1).
Pillar: 1.7 μm of C18 of ACQUITY UPLC BEH (50mm × 2.10mm)
Mobile phase: 0.1% aqueous formic acid and 0.1% formic acid methanol solution
Quantitative approach: internal standard method
Mpk: mg/kg
1, the change of pharmacokinetics of each drug after different way of administration (rat oral gavage or subcutaneous injection) is investigated
As a result referring to Fig. 1 and table 1, wherein Fig. 1 is each after different way of administration such as rat oral gavage or subcutaneous injection
The change of pharmacokinetics curve of drug, table 1 show each drug after different way of administration (rat oral gavage or subcutaneous injection)
Pharmacokinetic data (dabigatran concentration).
Table 1
From Fig. 1 and table 1 as can be seen that the half-life period for the dabigatran that subcutaneous administration generates in vivo be considerably longer than stomach-filling to
Medicine has especially achieved the effect that 2 times or more in the olive oil solvent formula of embodiment 2；And subcutaneous administration reaches in vivo
Than adding group exposed amount much higher than gastric infusion, 3~6 times are reached；Compared to gastric infusion, the Drug-time curve of subcutaneous administrations is more
Add gently, the blood concentration of internal dabigatran is more steady.
2, after detection is administered 8 hours under different way of administration (stomach-filling and subcutaneous administrations) and Different solution, in vivo
The blood concentration of dabigatran
Table 2 is shown under different way of administration (gastric infusion and subcutaneous injection), after administration 8 hours in rat plasma
Dabigatran concentration.
Table 2
From table 2 it can be seen that the dabigatran concentration in rat plasma under subcutaneous administrations approach significantly larger than fills
Stomach administration route.
3, the hypodermic pharmacokinetic data of various dose pharmaceutical composition compares (dabigatran concentration)
Table 3 shows the hypodermic pharmacokinetic data of various dose pharmaceutical composition (dabigatran concentration).
Table 3
From table 3 it can be seen that the dabigatran etcxilate pharmaceutical composition of the invention of subcutaneous administrations various dose, they
Internal dabigatran half-life period and exposed amount show good dose-effect relationship.
4, the medicine codes or data that different drugs are subcutaneously injected compares (dabigatran concentration)
Table 4 shows the different drugs of subcutaneous injection (the dabigatran etcxilate pharmaceutical composition of such as embodiment of the present invention 1 and right
The different dabigatran etcxilate injections of ratio 1~3) pharmacokinetic data (dabigatran concentration).
Table 4
From table 4, it can be seen that under subcutaneous administrations mode, pharmaceutical composition of the invention rat it is intracorporal up to than
The exposed amount of group is added to be above comparative example 1, comparative example 2 and comparative example 3.
5, long-term stable experiment
Long-term 12 months quality stability detection is carried out to product prepared by Examples 1 to 7 and comparative example 1~4, specifically
Detection method is referring to the Pharmacopoeia of the People's Republic of China 2005 editions second, as a result referring to table 5.
Table 5
The result shows that the indices of dabigatran etcxilate pharmaceutical composition of the invention meet relevant regulations, and it is better than
Drug made from comparative example 1~4.
6, safety testing
By product made from the embodiment of the present invention 1~7 and comparative example 1~4, according to existing drug registration laws and regulations requirement
(" Chemical induced irritation, anaphylaxis box hemolytic investigative technique guideline ") carry out vascular stimulation tests, hemolytic test,
Sensitivity test, the results show that the test sample of the embodiment of the present invention 1~7 meet vascular stimulation tests, hemolytic test and
The regulation of sensitivity test, and all indicators are better than the test samples of comparative example 1~4.For example, the embodiment of the present invention 1~7
Similar variation is presented in injection site skin, the vein of test sample, has no that hyperemia, oedema, scleroma and necrosis etc. are abnormal existing
As.
7, dissolubility is investigated
Product made from difference Example 1~7 and comparative example 1~4, adding water for injection, (additive amount is the 2 of sample weight
~5 times), it is recorded with stopwatch and redissolves the time, every batch of sample test 3 times, be averaged.The results show that injection of the invention reaches
Than adding group ester pharmaceutical composition to have faster clinical substantially acceptable redissolution performance, (the redissolution time of all test samples is equal
Between 15~50 seconds, solution clear free from admixture), (redissolved the time 60~90 seconds, and with particle better than comparative example 1~4
Object).
Claims (10)
1. a kind of injection dabigatran etcxilate pharmaceutical composition, which is characterized in that including following components:
(1) the active material dabigatran etcxilate as shown in Formulas I -2；
(2) pharmaceutically acceptable solvent；And be optionally present
(3) other pharmaceutically acceptable auxiliary materials.
2. pharmaceutical composition according to claim 1, which is characterized in that the pharmaceutically acceptable solvent includes injection
With water, physiological saline, PBS buffer solution or pharmaceutically acceptable oil phase solvent and their mixture.
3. pharmaceutical composition according to claim 2, which is characterized in that the pharmaceutically acceptable oil phase solvent choosing
From: olive oil, sesame oil, Emulsifier EL-60, peanut oil, polyethylene glycol, Solutol HS15, ethyl oleate,
And their mixture.
4. pharmaceutical composition according to claim 1, which is characterized in that pharmaceutically acceptable other auxiliary materials choosing
From: sodium chloride, glucose, glycerol, mannitol, lactose, trehalose, sodium carboxymethylcellulose, hypromellose, hydroxypropyl
Base-cyclodextrin, Tween 80, poloxamer, Tai Luoshamu, polyethylene glycol, Solutol HS15, PEG- cholesterol,
PEG- cholesterol derivative, PEG- vitamin A, PEG- vitamin E, vinylacetate, pyrrolidones, gelatin, casein, dextrorotation
Sugared acid anhydride 40, cholesterol, glycerine, colloidal silicon dioxide, gum arabic, tragacanth, peach gum, carbomer, stearic acid, stearic acid
Calcium, hexadecanol-octadecyl alcolol mixture, cetomacrogol emulsifying wax, sorbitan, polyoxyethylene alkyl ether, polyoxyethylene castor
Sesame oil derivative, polyoxyethylene sorbitan fatty acid esters, Myrj 45, phosphate, dodecyl sodium sulfonate
Sodium, carboxy-propyl cellulose, methylcellulose, hydroxyethyl cellulose, noncrystalline cellulose, hard acid magnalium, gathers calcium carboxymethylcellulose
Vinyl alcohol, dioctyl sulfosuccinate, sodium dialkyl sulfosuccinate, lauryl sodium sulfate, alkyl aryl polyether sulphur
Acid esters, the mixture of sucrose stearate and sucrose distearate, vinylpyrrolidone-methacrylic acid -2- dimethylamino
Ethyl ester dimethyl suflfate, amine, amine oxide, amine salt, triethanolamine, benzalkonium chloride, polymethyl methacrylate bromination trimethylammonium, bromine
Change dodecyltrimethylammonium, cetab, chlorination three (cetyl) methyl ammonium, alkyl-front three ammonium salt, dioxane
Base-diformazan ammonium salt, dodecyltrimethyl, alkyl dimethyl ammonium halide, bromination decyl trimethyl ammonium, bromination 12
Alkyl triethyl ammonium, Tetrabutylammonium bromide, bromination benzyltrimethylammon.um, quaternized polyoxyethanyl alkylamine, methylation quaternary ammonium are poly-
Close object, protonation quaternary ammonium acrylamide, brocide, cetyl pyridinium, acid imide pyrroles salt, sulphur
Compound, cation guar gum and their mixture.
5. pharmaceutical composition according to claim 1, which is characterized in that by weight percentage, active material Da Bijia
The content of group ester I-2 is the 0.001%~85% of injection dabigatran etcxilate pharmaceutical composition total weight, preferably 0.1%~
80%, more preferable 1%~50%；Remaining for pharmaceutically acceptable solvent and be optionally present pharmaceutically acceptable other are auxiliary
Material.
6. pharmaceutical composition according to claim 1, which is characterized in that described pharmaceutical composition is solid powder, particle
Object, freeze-dried powder or grease.
7. a kind of preparation method of injection dabigatran etcxilate pharmaceutical composition, which comprises the following steps:
The active material dabigatran etcxilate I-2 of recipe quantity is weighed, and other the pharmaceutically acceptable auxiliary materials being optionally present, to
Suitable pharmaceutically acceptable solvent is wherein added, stirring and dissolving continues to be added to recipe quantity, after mixing evenly, is added suitable
Amount medicinal carbon adsorbed, then use filtering with microporous membrane decarburization, then through filtering with microporous membrane degerming to get.
8. after filtration sterilization, carrying out frozen dried the method according to the description of claim 7 is characterized in that optional.
9. the method according to the description of claim 7 is characterized in that the additive amount of the medicinal carbon is overall solution volume
0.01%~0.5%, preferably 0.01%~0.5%, more preferable 0.1%~0.3%, most preferably 0.1%~0.2%, w/v.
10. the described in any item dabigatran etcxilate pharmaceutical compositions of claim 1~6 treat or prevent following illness in preparation
Purposes in medicament, the illness include:
(a) deep vein thrombosis and pulmonary embolism；And/or
(b) venous thromboembolism, acute coronary syndrome, acute deep venous thrombosis, pulmonary embolism and the recurrence formed
Deep vein thrombosis.
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| CN201710425912.7A CN109010249A (en) | 2017-06-08 | 2017-06-08 | Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710425912.7A CN109010249A (en) | 2017-06-08 | 2017-06-08 | Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application |
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|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020180489A1 (en) * | 2019-03-06 | 2020-09-10 | University Of Rochester | Anticoagulant compositions and uses thereof |
| CN113893356A (en) * | 2020-11-27 | 2022-01-07 | 上海博志研新药物技术有限公司 | Dabigatran etexilate mesylate inclusion compound, preparation method and application |
| CN114025746A (en) * | 2019-05-10 | 2022-02-08 | 福多兹制药公司 | Injectable polymeric nanoparticle compositions of antithrombotic agents and methods thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
-
2017
- 2017-06-08 CN CN201710425912.7A patent/CN109010249A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020180489A1 (en) * | 2019-03-06 | 2020-09-10 | University Of Rochester | Anticoagulant compositions and uses thereof |
| CN114025746A (en) * | 2019-05-10 | 2022-02-08 | 福多兹制药公司 | Injectable polymeric nanoparticle compositions of antithrombotic agents and methods thereof |
| CN114025746B (en) * | 2019-05-10 | 2023-08-25 | 福多兹制药公司 | Injectable polymer nanoparticle compositions of antithrombotic agents and methods thereof |
| CN113893356A (en) * | 2020-11-27 | 2022-01-07 | 上海博志研新药物技术有限公司 | Dabigatran etexilate mesylate inclusion compound, preparation method and application |
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Application publication date: 20181218 |